AB1764-HPR EXPRESSION OF CYTOKINES RELATED TO “INFLAMMAGING” AND ARTERIAL STIFFNESS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS: A GENE ONTOLOGY AND PATHWAY ENRICHMENT ANALYSIS
Authors: J. Carvajal-Veloza, J. A. Rubio-Rubio, G. Salguero, L. D. Gutiérrez-Castañeda, G. S. Rodríguez-Vargas, P. Santos-Moreno, D. Echeverri, P. K. Bautista-Niño, L. Saenz, A. Rojas-Villarraga
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Cardiovascular disease is the leading cause of premature death among patients with rheumatoid arthritis (RA). Inflammatory cytokines play a pivotal role in this process, leading to impaired artery elasticity by priming endothelial dysfunction and enhanced arterial stiffness. <h3>Objectives</h3> To assess the expression of inflammatory cytokines associated to cardiovascular alterations such as arterial stiffness among patients with RA and osteoarthritis (OA) through Gene Ontology and Pathway Enrichment analysis. <h3>Methods</h3> Inclusion criteria for this analytical cross-sectional study were patients with RA and OA between 40 and 70 years old. Sociodemographic and clinical characteristics as well as inflammatory, metabolic markers, acute phase reactants, autoantibodies were analyzed. Levels of 18 cytokine: including VCAM1 (CD106), ICAM1(CD54), CCL7 (MARC), MCP1, SPP1 (OPN), PDGF, CXCL10 and inflammaging related cytokines: INF- γ (IFNG), IL-10, IL-1RA, IL-1β, IL-6, TNF-α, MMP1, MMP2, MMP9, TIMP-1, TIMP2, were measured using a Luminex Assay (Invitrogen, Carlsbad, CA, United States). Cardiovascular measurements (Including Pulse Wave Velocity -PWV and aortic augmentation index – Aix) were performed within one month after blood sampling using the TensioMed Arteriography. A protein-protein interaction network (PPI) was built using the string App plugin from Cytoscape v3.9.1. Gene Ontology and pathway analysis were carried out using ClueGO (v2.8.9) + Cluepedia (v1.5.9) Cytoscape plugin for the proteins that showed a significant overexpression against GO biological processes, KEGG, and Reactome pathways databases (<i>Homo sapiens</i>). <h3>Results</h3> A total of eighty patients were included (71.3% women). The average age was 57 years, interquartile range (IQR) 10. OA patients had higher waist circumference, weight, and body mass index values than RA patients. There were no differences in lipid profile or glucose levels. CRP levels were higher in RA patients. Levels of disease activity in RA patients was low according to the measurement of the DAS-28-PCR. 12.5% of patients with RA had polyautoimmunity. There were no significant differences in the measurement of cardiovascular variables between the two groups except for Brachial diastolic blood pressure, which was higher in the RA group (p=0,049). Plasma levels of VCAM1 (CD106;), MARC (CCL7; p=0.000), OPN (SPP1; 0.040), IL-1RA; p=0.015) and IL-1β (p=0.031) were significantly higher in the group of RA patients. ICAM1 (CD54), MARC, and INF-γ levels were correlated with Aix in the RA group. In the OA group, IL-10 levels positively correlated with Brachial pulse pressure and other central and peripheral pressure measurements (mild or moderate). The merged network between upregulated cytokines (VCAM1, SPP1, PDGF1, IFNG, ICAM1 and CCL7), RA query in DISESASE database and "Arterial stiffness" query (PubMed) resulted in a PPI network with 26 nodes and 88 interactions. (Figure 1.) The nodes with BC above 0.05 (VCAM1, TNF, JAK1, ICAM1, IL-10, CD4, PTK2B, FN1, ITGB1) represents the key genes. Ten <i>GO</i> terms and twelve pathways were significantly enriched (Figure 2). The principal GO terms were as follows: "membrane to membrane docking" (34% genes), "response to type II interferon" (7.89% genes), and "regulation of lipid biosynthetic process" (5.26% genes). KEGG and REACTOME included: signaling by PDGF (7.89%), integrin cell surface interaction (2.63%), extracellular matrix organization (2.63%). <h3>Conclusion</h3> Cytokines related to "Inflammaging" shown significant relationship with arterial stiffness parameters measured in RA patients and IL-10 in OA group. These representative nodes/proteins were related with cellular adhesion, MAPK activation pathway and proinflammatory responses showing that those are key processes in arterial stiffness and rheumatoid arthritis. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Jonathan Carvajal-Veloza: None declared, Jaime-Andrés Rubio-Rubio: None declared, Gustavo Salguero: None declared, Luz-Dary Gutiérrez-Castañeda: None declared, Gabriel-Santiago Rodríguez-Vargas: None declared, Pedro Santos-Moreno Speakers bureau: Abbvie, Abbott, Biopas-UCB, Bristol, Janssen, Pfizer, Roche, Sanofi, Grant/research support from: Abbvie, Abbott, Biopas-UCB, Bristol, Janssen, Pfizer, Roche, Sanofi, Dario Echeverri: None declared, Paula-Katherine Bautista-Niño: None declared, Luis Saenz: None declared, Adriana Rojas-Villarraga: None declared.